An estimated 5.7 million people in the U.S. have heart failure and more than 292,000 die from heart failure-related complications each year. While much is known about the mechanisms of cardiac hypertrophic growth and subsequent decompensation leading to failure, few therapeutic strategies are available, and these are aimed primarily at relieving symptoms, preventing hospitalization, and improving the quality of life of patients, with little overall effect on mortality. Recent research has provided new insights into the molecular signaling pathways involved in the progression of the disease;however, heart failure remains a complex multifactorial problem. A comprehensive mechanistic understanding of heart failure requires not just elucidation of targets/pathways modified during the progression of the disease, but an integrative understanding of how alterations at the level of genes and proteins affect the sophisticated interplay between the electrophysiological, Ca2+ handling, and energetic subsystems of the cardiac cell. This proposal brings together leaders in the areas of excitation-contraction coupling, mitochondrial biology, redox modulation, proteomics, and computational biology to investigate how the remodeling of ion transport pathways and mitochondrial proteins contribute to maladaptive responses in a pressure-overload model of hypertrophy, which progresses to heart failure over several weeks. The central hypothesis to be explored is that alterations in Ca2+m dynamics not only contribute to impaired energy supply and demand matching following pressure-overload, but also significantly compromise the pathways responsible for handling reactive oxygen (ROS) and nitrogen (RNS) species in the mitochondria and the cell. This imbalance results in ROS/RNS-dependent modifications of key proteins involved in EC coupling and mitochondrial oxidative phosphorylation, with concomitant effects on function that contribute to cellular injury or death. A vicious circle of these complex deleterious interactions could thus mediate decompensation of the failing heart. (End of Abstract)